Cardiac metabolic remodeling drives dicarbonyl stress-induced mitochondrial dysfunction in experimental heart failure with preserved ejection fraction.

Abstract

Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin II (1.5 μg/g/day) and phenylephrine (50 μg/g/day) in 8- to 10-wk-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by an ∼20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by sevenfold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and antiglycation strategies as promising therapeutic avenues.Recent studies increasingly highlight profound metabolic remodeling within the HFpEF heart; however, it remains unclear if this is an intrinsic or systemic phenomenon. In the present study, we identify dicarbonyl and glycative stress as key drivers of mitochondrial dysfunction in an ANGII/PE mouse model with HFpEF phenotype independent of systemic metabolic disease. These findings reveal a previously unrecognized metabolic-mitochondrial axis and suggest dicarbonyl detoxification and mitochondrial antiglycation as potential therapeutic targets.